An interventional study of Standardized Fortification and Adjustable Fortification in Very Preterm Maturity of Infant and Very Low Birth Weight Infant, sponsored by Children's National Research Institute. Recruiting at 1 site in United States. Open to participants aged Up to 4 Weeks. Per ClinicalTrials.gov, last updated 2025-07-11.
Sponsored by Children's National Research Institute · Not applicable, Interventional, and Supportive care
Human milk has several well-established benefits but does not adequately meet the increased nutritional demands of the growing preterm infant, necessitating additional nutrient supplementation in a process known as fortification. In U.S. neonatal intensive care units (NICUs), human milk is primarily supplemented using standardized fortification, in which a multicomponent fortifier is added to human milk to achieve assumed nutrient content based on standard milk reference values. However, this method does not account for the significant variability in human milk composition or in preterm infant metabolism, and up to half of all very premature infants experience poor growth and malnutrition using current nutritional practices. Poor postnatal growth has adverse implications for the developing preterm brain and long-term neurodevelopment.
Recent advances allow for individualized methods of human milk fortification, including adjustable and targeted fortification. Adjustable fortification uses laboratory markers of protein metabolism (BUN level) to estimate an infant's protein requirements. In targeted fortification, a milk sample is analyzed to determine its specific macronutrient and energy content, with additional macronutrient supplementation provided as needed to achieve goal values. Emerging data suggest that both methods are safe and effective for improving growth, however information on their comparable efficacy and neurodevelopmental implications are lacking, particularly using advanced quantitative brain MRI (qMRI) techniques.
Through this prospective, randomized-controlled trial, the investigators will compare the impact of individualized human milk fortification on somatic growth and neurodevelopment in preterm infants. Infants will be randomized to receive one of three nutritional interventions: standardized (control group), adjustable, or targeted human milk fortification. Infants will undergo their assigned nutritional intervention until term-equivalent age or discharge home, whichever is achieved first. Brain qMRI will be performed at term-corrected age, and neurodevelopmental follow-up will be performed through 5 years of age.
Children's National Research Institute is the lead sponsor of 124 studies on the registry; 45 are open to participants now.
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Exclusion Criteria:
All study participants will undergo feed advancement and fortification with liquid, bovine-based human milk fortifier (HMF) to an assumed human milk content of 24kcal/oz per the Children's National Hospital NICU standardized clinical feeding protocol. The same milk fortification recipes are utilized for mother's own milk (MOM) and donor human milk (DHM). Each infant's growth trajectory is monitored (weight, length, and head circumference) with dietary modifications performed as needed based on growth parameters. Growth failure is defined as a decline in weight-for-age z-score by greater than 1 standard deviation (\>1 SD) beginning 1 week after reaching goal fortified feeds. For infants who demonstrate growth failure, Step 1 will be to add medium chain triglyceride (MCT) oil. If growth remains sub-optimal, Step 2 will be to add liquid protein.
Dietary Supplement: Standardized Fortification
Adjustable fortification will begin 1 week after tolerating goal feeds of standardized fortification. Blood urea nitrogen (BUN) level as a marker of protein metabolism will be measured weekly, and supplementation with liquid protein will be adjusted as necessary to maintain a goal BUN level between 9-14mmol/dL, up to a maximum assumed protein intake of 4.5 g/kg/day. Liquid protein supplementation will be modified as follows: * BUN Level \<9 mmol/dL: Increase by 0.5g/kg/day * BUN Level 9-14 mmol/dL: No change * BUN Level \>14 mmol/dL: Decrease by 0.25g/kg/day * BUN Level \>20 mmol/dL: Hold for 1 week and re-assess Growth failure is defined as a decline in weight-for-age z-score by \>1 SD beginning 1 week after achieving BUN within goal range from adjustable fortification. For infants who demonstrate growth failure, MCT oil will be added and increased weekly as needed.
Dietary Supplement: Standardized Fortification · Dietary Supplement: Adjustable Fortification
Targeted fortification will begin 1 week after tolerating goal feeds of standardized fortification. Additional supplementation with liquid protein and/or MCT oil will be provided based on twice weekly milk analysis using a mid-infrared human milk analyzer in order to meet macronutrient (carbohydrate, protein, lipid) and energy intake goals per pediatric nutrition guidelines (protein 4-4.5g/kg/day, fat 6-8g/kg/day, energy 120-130kcal/kg/day). Growth failure is defined as a decline in weight-for-age z-score by \>1 SD beginning 1 week after receiving macronutrient and energy intake within goal range from targeted fortification. For infants with growth failure, total energy intake will be increased with additional protein and/or MCT oil supplementation. Energy intake may be increased weekly as needed.
Dietary Supplement: Standardized Fortification · Dietary Supplement: Adjustable Fortification
Fortification with liquid, bovine-based HMF to assumed human milk content of 24kcal/oz
Additional liquid protein supplementation to maintain serum BUN levels within goal range (9-14mmol/dL)
Additional liquid protein and/or MCT oil supplementation to maintain protein, fat, and energy intake within goal range based upon mid-infrared human milk analysis
Weight Gain Velocity
Weight gain velocity (grams per kilogram per day)
Time frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Length Growth Velocity
Length growth velocity (centimeters per week)
Time frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Head Circumference Growth Velocity
Head circumference growth velocity (centimeters per week)
Time frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Total and Regional Brain Volumes
Total and regional (cortical and deep gray matter, white matter, amygdala-hippocampus, brainstem, cerebellum) brain volumes by MRI
Time frame: Term-equivalent age (38 to 41 weeks postmenstrual age)
Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)
Summary scores in 13 different domains (habituation, attention, handling, self-regulation, arousal, excitability, lethargy, hypertonicity, hypotonicity, non-optimal reflex, asymmetric reflex, quality of movement, stress)
Time frame: Term-equivalent age (38 to 41 weeks postmenstrual age)
Mullen Scales of Early Learning (MSEL)
Composite score as well as 5 subscores: gross motor, fine motor, visual reception, receptive language, and expressive language (reported as standardized t-scores, higher score indicates a better outcome, mean standardized t-score of 50 with standard deviation of 10)
Time frame: 18 months corrected age
Mullen Scales of Early Learning (MSEL)
Composite score as well as 5 subscores: gross motor, fine motor, visual reception, receptive language, and expressive language (reported as standardized t-scores, higher score indicates a better outcome, mean standardized t-score score of 50 with standard deviation of 10)
Time frame: 36 months (3 years) of age
Wechsler Preschool and Primary Scale of Intelligence (4th edition) (WPPSI-IV)
Five primary indices: verbal comprehension, visual spatial, working memory, fluid reasoning, and processing speed (higher score indicates better performance, score range 40 to 160)
Time frame: 60 months (5 years) of age
Differential Abilities Scale (2nd edition)-(DAS-II)
\*For children with significant delays who may be unable to reach basal scores on the WPPSI-IV Early years core battery: verbal, nonverbal, and spatial reasoning subtests (higher score indicates better performance, score range 40-170)
Time frame: 60 months (5 years) of age
Plan to share: No
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